This invention relates to pharmaceutically acceptable amide and imide derivatives of low molecular weight terpolymers of butyl vinyl ether, maleic anhydride and maleimide having antitumor activity.
Copolymers of alkyl vinyl ethers and maleic anhydride are known in the art as are the amide and imide derivatives thereof. These are generally high molecular weight resins useful in non-pharmaceutical applications such as binders, coatings, elastomers, paper, textiles and the like products. For example, U.S. Pat. No. 2,313,565 describes the preparation of such resins by the catalyzed polymerization of ethyl vinyl ether and maleic anhydride from which the amide and imide derivatives are then made by further reaction with ammonia or with aliphatic and aromatic amines. U.S. Pat. 2,944,033 describes similar such production of amides and imides by ammoniation of copolymers of methyl vinyl ether and maleic anhydride.
Butyl vinyl ether and maleic anhydride are included in extensive lists of various monomeric components of copolymers which can be ammoniated to amides and imides in U.S. Pat. Nos. 3,157,595 and 3,998,907. The disclosed use of these derivatized copolymers is for clarification of water and for preparation of elastomeric products, respectively.
Use of maleimide-containing monomeric substances as dibasic acid components for reaction with olefins, or as a third component to replace part of the anhydride component in the copolymerization of olefins and polycarboxylic anhydrides, is described in Canadian Pat. No. 664,326 and U.S. Pat. No. 3,157,595, respectively. However, no specific maleimide-containing polymers are made or described in these patents.
Pharmaceutically active copolymers of divinyl ether and maleic anhydride are known such as those described in U.S. Pat. Nos. 3,224,943 and 3,794,622 and by Breslow in Pure & Appl. Chem. 46, 103-113 (1976). However, these polymeric materials are relatively high molecular weight substances of 5000 and greater molecular weight.
Low molecular weight copolymers with both amide and imide functionality and having antitumor properties are described in U.S. Pat. No. 4,255,537. The base copolymer is prepared by copolymerization of maleic anhydride and other polycarboxylic anhydrides with alkenes such as ethylene and propylene as distinguished from alkenyl oxides such as vinyl ethers. The base copolymer molecular weight ranges from about 300 to about 1500 and the imide comprises about 5 wt. % to about 40 wt. % of the derivatized groups.
Hodnett et al., J. Med. Chem. 21 (7), 52-657 (1978), describe the antitumor activity of copolymers of isobutyl vinyl ethers and acrylic acid against Sarcoma 180. The disclosed molecular weights from viscosity measurements range from 49,000 to 250,000 (Table II).